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Vaccine Therapy With or Without Cyclophosphamide in Treating Patients Who Have Undergone Surgery for Stage II, Stage III, or Stage IV Melanoma

A Multicenter Trial to Evaluate the Effects of Administration of Cyclophosphamide and Melanoma-Derived Helper Peptides on the Immunogenicity of a Class I MHC-Restricted Peptide-Based Vaccine in Participants With Resected Melanoma

Status
Completed
Phases
Phase 1Phase 2
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00118274
Enrollment
170
Registered
2005-07-11
Start date
2005-03-31
Completion date
2010-02-28
Last updated
2021-04-20

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Melanoma (Skin)

Keywords

stage II melanoma, stage III melanoma, stage IV melanoma

Brief summary

RATIONALE: Vaccines made from peptides may help the body build an effective immune response to kill tumor cells. Drugs used in chemotherapy, such as cyclophosphamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Cyclophosphamide may also stimulate the immune system in different ways and stop tumor cells from growing. Giving vaccine therapy together with cyclophosphamide after surgery may cause a stronger immune response to kill any remaining tumor cells. It may also prevent or delay the recurrence of melanoma. PURPOSE: This randomized phase I/II trial is studying the side effects of vaccine therapy when given with or without cyclophosphamide and to see how well they work in treating patients who have undergone surgery for stage II, stage III, or stage IV melanoma.

Detailed description

OBJECTIVES: Primary * Determine the safety of adjuvant vaccine therapy comprising multi-epitope melanoma peptides (MP) and multi-epitope melanoma helper peptides (MHP) emulsified in Montanide ISA-51 in patients with resected stage IIB-IV melanoma. * Determine the safety of administering cyclophosphamide before vaccination in these patients. * Compare the magnitude of immune response against vaccination comprising MP in combination with either MHP or tetanus toxoid helper peptide (TET) emulsified in Montanide ISA-51 with vs without cyclophosphamide in these patients. Secondary * Compare the response rate and persistence of immune responses in patients treated with these regimens. * Compare the magnitude of immune response against vaccination comprising TET or MHP with vs without cyclophosphamide in these patients. * Compare the response rate and persistence of immune response against vaccination comprising TET or MHP with vs without cyclophosphamide in these patients. * Determine the delayed-type hypersensitivity response to the peptide components of these vaccines in these patients. * Compare, preliminarily, disease-free survival of patients treated with these regimens. OUTLINE: This is a randomized, open-label, multicenter study. Patients are stratified according to HLA-type (HLA-A1 positive vs HLA-A2 positive, HLA-A1 negative, or -A3 negative vs HLA-A3 positive, or -A1 negative) and participating center (University of Virginia \[UVA\] vs non-UVA). Patients are randomized to 1 of 4 treatment arms. * Arm I: Patients receive vaccine comprising multi-epitope melanoma peptides (MP) and tetanus toxoid helper peptide emulsified in Montanide ISA-51 intradermally (ID) and subcutaneously (SC) on days 1, 8, 15, 29, 36, 43, 85, 183, 274, and 365. * Arm II: Patients receive cyclophosphamide IV over 30-60 minutes on day -4. Patients then receive vaccine as in arm I. * Arm III: Patients receive vaccine comprising MP and multi-epitope melanoma helper peptides emulsified in Montanide ISA-51 ID and SC on days 1, 8, 15, 29, 36, 43, 85, 183, 274, and 365. * Arm IV: Patients receive cyclophosphamide as in arm II. Patients then receive vaccine as in arm III. Treatment in all arms continues in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed every 6 months for 2 years and then annually thereafter. PROJECTED ACCRUAL: A total of 173 patients will be accrued for this study within 2 years.

Interventions

BIOLOGICALincomplete Freund's adjuvant

Given intradermally and subcutaneously

Given intradermally and subcutaneously

Given intradermally and subcutaneously

Given intradermally and subcutaneously

DRUGcyclophosphamide

Given IV

Sponsors

National Cancer Institute (NCI)
CollaboratorNIH
Craig L Slingluff, Jr
Lead SponsorOTHER

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE

Eligibility

Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No

Inclusion criteria

DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed melanoma * Cutaneous, mucosal, or primary melanoma * Stage IIB-IV disease * Has undergone surgical resection or stereotactic radiosurgery for malignant melanoma ≥ 1 week but ≤ 6 months ago * No clinical or radiological evidence of disease after surgical resection or stereotactic radiosurgery by chest x-ray or CT scan\*, abdominal and pelvic CT scan\*, and head CT scan or MRI NOTE: \*Positron emission tomography scan/CT fusion scan may replace scans of the chest, abdomen, and pelvis * Must have ≥ 2 intact (undissected) axillary and/or inguinal lymph node basins * HLA-A1, -A2, or -A3 positive AND HLA-DR1, -DR4, -DR11, -DR13, or -DR15 positive * Ineligible for OR refused interferon * No ocular melanoma * Brain metastases allowed provided all of the following criteria are met: * No more than 3 total brain metastases * Each metastasis ≤ 2 cm in diameter at the time of study entry * Each metastasis was completely removed by surgery or treated with stereotactic radiosurgery * No evidence of brain metastasis progression since the most recent treatment PATIENT CHARACTERISTICS: Age * 18 and over Performance status * ECOG 0-1 Life expectancy * Not specified Hematopoietic * Absolute neutrophil count \> 1,000/mm\^3 * Platelet count \> 100,000/mm\^3 * Hemoglobin \> 9 g/dL Hepatic * AST and ALT ≤ 2.5 times upper limit of normal (ULN) * Bilirubin ≤ 2.5 times ULN * Lactic dehydrogenase ≤ 1.5 times ULN * Alkaline phosphatase ≤ 2.5 times ULN * Hepatitis C negative Renal * Creatinine ≤ 1.5 times ULN Cardiovascular * No New York Heart Association class III or IV heart disease Immunologic * HIV negative * No known or suspected allergy to any component of the study vaccines * No autoimmune disorder with visceral involvement * No prior or active autoimmune disorder requiring cytotoxic or immunosuppressive therapy * The following immunologic conditions are allowed: * Laboratory evidence of autoimmune disease (e.g., positive anti-nuclear antibody titer) without symptoms * Clinical evidence of vitiligo * Other forms of depigmenting illness * Mild arthritis requiring non-steroidal anti-inflammatory drugs Other * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * Weight ≥ 110 lbs * No uncontrolled diabetes * Hemoglobin A1C \< 7% * No medical contraindication or potential problem that would preclude study compliance * No other malignancy except squamous cell or basal cell skin cancer without known metastasis, carcinoma in situ of the breast (ductal or lobular) or cervix, or other successfully treated cancer without distant metastasis with no evidence of recurrence or metastasis for \> 5 years * No known active addiction to alcohol or drugs * No recent (within the past year) or ongoing illicit IV drug use PRIOR CONCURRENT THERAPY: Biologic therapy * No prior vaccination with any of the synthetic peptides used in this study * Prior vaccinations (containing agents other than the synthetic peptides used in this study) that resulted in recurrent disease during or after vaccine administration allowed provided the last vaccination was administered more than 12 weeks ago * More than 4 weeks since prior and no concurrent interferon (e.g., Intron-A®), interleukins (e.g., Proleukin®), or growth factors (e.g., Procrit®, Aranesp®, or Neulasta®) * More than 4 weeks since prior and no concurrent allergy desensitization injections * No influenza vaccines for at least 2 weeks before or after study vaccine administration Chemotherapy * More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas) * No concurrent chemotherapy, including nitrosoureas Endocrine therapy * More than 4 weeks since prior and no concurrent oral or parenteral corticosteroids * No prior or concurrent inhaled steroids (e.g., Advair®, Flovent®, or Azmacort®) * Prior or concurrent topical corticosteroids allowed Radiotherapy * See Disease Characteristics * More than 4 weeks since other prior and no concurrent radiotherapy Surgery * See Disease Characteristics Other * More than 4 weeks since prior and no other concurrent investigational agents * More than 30 days since prior and no concurrent participation in another clinical study

Design outcomes

Primary

MeasureTime frameDescription
Safety of the Peptide Vaccines30 days after receiving the last dose of study drug, up to week 52Number of participants with dose-limiting toxicities

Secondary

MeasureTime frameDescription
Immunogenicity (CD8+ T Cell Response to 12 Melanoma Peptides, 12MP) as Measured by Elispot Assay, up to Day 5050 daysThe primary end point was the maximum cumulative circulating CD8+ T cell response to 12 melanoma peptides (12MP) measured by ELISpot assay over the first six vaccines (to day 50).

Countries

United States

Participant flow

Participants by arm

ArmCount
Arm I
Patients receive vaccine comprising multi-epitope melanoma peptides, tetanus toxoid helper peptide emulsified in Montanide ISA-51 intradermally and subcutaneously on days 1, 8, 15, 29, 36, 43, 85, 183, 274, and 365. incomplete Freund's adjuvant: Given intradermally and subcutaneously multi-epitope melanoma peptide vaccine: Given intradermally and subcutaneously tetanus toxoid helper peptide: Given intradermally and subcutaneously
41
Arm II
Patients receive cyclophosphamide IV over 30-60 minutes on day -4. Patients then receive vaccine comprising multi-epitope melanoma peptides, tetanus toxoid helper peptide emulsified in Montanide ISA-51 intradermally and subcutaneously on days 1, 8, 15, 29, 36, 43, 85, 183, 274, and 365. incomplete Freund's adjuvant: Given intradermally and subcutaneously multi-epitope melanoma peptide vaccine: Given intradermally and subcutaneously tetanus toxoid helper peptide: Given intradermally and subcutaneously cyclophosphamide: Given IV
43
Arm III
Patients receive vaccine comprising melanoma peptides and multi-epitope melanoma helper peptides emulsified in Montanide ISA-51 intradermally and subcutaneously on days 1, 8, 15, 29, 36, 43, 85, 183, 274, and 365. incomplete Freund's adjuvant: Given intradermally and subcutaneously melanoma helper peptide vaccine: Given intradermally and subcutaneously multi-epitope melanoma peptide vaccine: Given intradermally and subcutaneously
42
Arm IV
Patients receive cyclophosphamide IV over 30-60 minutes on day -4. Patients then receive vaccine comprising melanoma peptides and multi-epitope melanoma helper peptides emulsified in Montanide ISA-51 intradermally and subcutaneously on days 1, 8, 15, 29, 36, 43, 85, 183, 274, and 365. incomplete Freund's adjuvant: Given intradermally and subcutaneously melanoma helper peptide vaccine: Given intradermally and subcutaneously multi-epitope melanoma peptide vaccine: Given intradermally and subcutaneously cyclophosphamide: Given IV
44
Total170

Baseline characteristics

CharacteristicArm IArm IIArm IIIArm IVTotal
Age, Categorical
<=18 years
0 Participants0 Participants0 Participants0 Participants0 Participants
Age, Categorical
>=65 years
11 Participants13 Participants9 Participants12 Participants45 Participants
Age, Categorical
Between 18 and 65 years
30 Participants30 Participants33 Participants32 Participants125 Participants
Sex: Female, Male
Female
13 Participants17 Participants13 Participants13 Participants56 Participants
Sex: Female, Male
Male
28 Participants26 Participants29 Participants31 Participants114 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
EG002
affected / at risk
EG003
affected / at risk
deaths
Total, all-cause mortality
0 / 410 / 430 / 420 / 44
other
Total, other adverse events
41 / 4143 / 4341 / 4244 / 44
serious
Total, serious adverse events
0 / 410 / 430 / 420 / 44

Outcome results

Primary

Safety of the Peptide Vaccines

Number of participants with dose-limiting toxicities

Time frame: 30 days after receiving the last dose of study drug, up to week 52

Population: Intent to treat population including 167 eligible and 3 ineligible.

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Arm ISafety of the Peptide Vaccines4 Participants
Arm IISafety of the Peptide Vaccines7 Participants
Arm IIISafety of the Peptide Vaccines2 Participants
Arm IVSafety of the Peptide Vaccines1 Participants
Secondary

Immunogenicity (CD8+ T Cell Response to 12 Melanoma Peptides, 12MP) as Measured by Elispot Assay, up to Day 50

The primary end point was the maximum cumulative circulating CD8+ T cell response to 12 melanoma peptides (12MP) measured by ELISpot assay over the first six vaccines (to day 50).

Time frame: 50 days

Population: All eligible participants, total = 167.

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
Arm IImmunogenicity (CD8+ T Cell Response to 12 Melanoma Peptides, 12MP) as Measured by Elispot Assay, up to Day 5032 Participants
Arm IIImmunogenicity (CD8+ T Cell Response to 12 Melanoma Peptides, 12MP) as Measured by Elispot Assay, up to Day 5029 Participants
Arm IIIImmunogenicity (CD8+ T Cell Response to 12 Melanoma Peptides, 12MP) as Measured by Elispot Assay, up to Day 508 Participants
Arm IVImmunogenicity (CD8+ T Cell Response to 12 Melanoma Peptides, 12MP) as Measured by Elispot Assay, up to Day 5012 Participants

Source: ClinicalTrials.gov · Data processed: Feb 21, 2026